US5294630A - Treatment of inflammatory bowel disease - Google Patents

Treatment of inflammatory bowel disease Download PDF

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Publication number
US5294630A
US5294630A US07/909,852 US90985292A US5294630A US 5294630 A US5294630 A US 5294630A US 90985292 A US90985292 A US 90985292A US 5294630 A US5294630 A US 5294630A
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US
United States
Prior art keywords
compound
carboxylic acid
formulation
disease
salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
US07/909,852
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English (en)
Inventor
David Blake
Peter P. K. Ho
Jill A. Panetta
David Rampton
Nicola Simmonds
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
London Hospital Medical College
Eli Lilly and Co
Original Assignee
London Hospital Medical College
Eli Lilly and Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by London Hospital Medical College, Eli Lilly and Co filed Critical London Hospital Medical College
Priority to US07/909,852 priority Critical patent/US5294630A/en
Priority to ZA934740A priority patent/ZA934740B/xx
Priority to CA002099789A priority patent/CA2099789A1/en
Priority to AU41758/93A priority patent/AU672977B2/en
Priority to JP5166779A priority patent/JPH06157310A/ja
Priority to ES93305298T priority patent/ES2090875T3/es
Priority to AT93305298T priority patent/ATE139440T1/de
Priority to EP93305298A priority patent/EP0578477B1/en
Priority to DK93305298.7T priority patent/DK0578477T3/da
Priority to DE69303234T priority patent/DE69303234T2/de
Assigned to LONDON HOSPITAL MEDICAL COLLEGE, ELI LILLY AND COMPANY reassignment LONDON HOSPITAL MEDICAL COLLEGE ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HO, PETER P. K., PANETTA, JILL A., BLAKE, DAVID, RAMPTON, DAVID, SIMMONDS, NICOLA
Application granted granted Critical
Publication of US5294630A publication Critical patent/US5294630A/en
Priority to GR960402479T priority patent/GR3021114T3/el
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention belongs to the fields of pharmaceutical chemistry and gastroenterology, and provides a method of treating, or preventing the recurrence of, inflammatory bowel disease, and reducing the risk of cancer in inflammatory bowel disease, making use of a series of phenylpyrazoles and phenylisothiazoles.
  • IBD Inflammatory bowel disease
  • UC ulcerative colitis
  • CD Crohn's disease
  • UC ulcerative colitis
  • the symptoms of each disease are characterized by periods of relapse and remission over many years.
  • the principal symptoms of UC are diarrhea and rectal bleeding. These symptoms may occur in CD of the colon, but when other areas of the bowel are involved, CD tends to cause abdominal pain, weight loss, malaise, fever, and malabsorption as well as diarrhea.
  • CD more commonly than UC, strictures, fistulas and abscesses within the abdominal cavity may occur.
  • UC and CD Medical treatment of UC and CD is similar and at present unsatisfactory. Active relapses are usually treated with corticosteroids (intravenous, orally or topically) with their attendant side-effects. Sulphasalazine and its derivatives (5-aminosalicylic acid) can be used in active disease and are effective in reducing the incidence of relapse in UC; all have occasionally troublesome side effects. Immunosuppressive agents such as azathioprine and 6-mercaptopurine are used in patients not responding to steroids or sulphasalazine and again have adverse effects. When currently available medical therapy fails, surgical resection of affected bowel is necessary, but this is not curative in CD as disease frequently recurs in residual intestine.
  • ROM reactive oxygen metabolites
  • ROMs are instrumental in the pathogenesis of both ulcerative colitis and Crohn's disease, and that the severity of the disease is related to the extent of their over-production. Antioxidant therapy or agents preventing or blocking the formation of ROMs can therefore prove beneficial.
  • sulphasalazine and its derivatives may work in IBD, at least in part, by scavenging ROMs.
  • Yamada et al. Antioxidant Properties of 5-Aminosalicylic Acid: Potential Mechanism for its Antiinflammatory Activity. In Williams, Ed., Trends in IBD Therapy, Lancaster: Klumer Acad. Publ., 73-84 (1990); Ahnfelt-Ronne et al., cited above.
  • ADPRT adenosine diphosphate ribosyl transferase
  • the present invention provides a method for treating or preventing the recurrence of inflammatory bowel disease comprising administering to a patient in need thereof an effective dose of a compound of the formula ##STR1## wherein X is a sulfur atom, a nitrogen atom, or a methyl-substituted nitrogen atom;
  • R is hydrogen, amino, C 1 -C 3 alkylamino, or hydroxy
  • R 1 is hydroxy, or OM
  • M is a nontoxic cation
  • R 2 and R 3 independently represent hydrogen, halo, C 1 -C 3 alkyl, trifluoromethyl, or C 1 -C 3 alkoxy.
  • the invention also provides the use of compounds of formula I for treating or preventing the recurrence of inflammatory bowel disease, including preventing colorectal cancer resulting from and in conjunction with IBD, and further provides pharmaceutical formulations which are adapted for that purpose.
  • the group X can be a sulfur atom, a nitrogen atom or a methyl-substituted nitrogen atom.
  • the isothiazole and pyrazole rings are both aryl, that is, fully unsaturated, the location of the double bonds in those rings depends on the nature of the X group, as will be readily understood by the reader. The various possible configurations of that ring are well explained and exemplified in the three Beck et al. patents.
  • the carboxylic acid group on the pyrazole or isothiazole ring may exist as the acid itself, or as a salt, in which the cation of the salt is represented by M.
  • Pharmaceutical chemists often prepare such drugs as alkali metal salts, wherein M would be sodium, potassium or lithium.
  • M can also be alkaline earth cations such as magnesium or calcium, a nontoxic metal cation such as aluminum or zinc, or an ammonium ion such as piperazinium, butyltrimethylammonium, piperidinium, phenyl-triethylammonium and the like.
  • the preferred salt-forming moieties include alkali metals and quaternary ammonium groups. More particularly, sodium, potassium, lithium, and quaternary ammonium groups wherein the nitrogen atom is substituted with four hydrogen, C 1 -C 18 alkyl, phenyl or benzyl moieties are preferred.
  • quaternary ammonium groups such as ammonium, tetramethylammonium, diethyl-dimethylammonium, diethyl-dibutylammonium, benzyltrimethylammonium, t-butyl-trimethylammonium, phenyl-triethylammonium, diethyldipropylammonium, s-butyl-trimethylammonium, isobutyltriethylammonium, dimethyl-bis(tetradecyl)ammonium, trimethyl-octadecylammonium, diethyl-decyl-heptadecylammonium and the like are useful and may be chosen for convenience in the circumstances.
  • X is a sulfur atom
  • X is a nitrogen atom
  • X is a methyl-substituted nitrogen atom
  • R is hydrogen or amino
  • R is amino or alkylamino
  • R is hydroxy or hydrogen
  • R 1 is hydroxy
  • R 1 is OM
  • M is a metal ion
  • M is an ammonium ion
  • R 2 and R 3 independently represent hydrogen, halo or trifluoromethyl
  • R 2 is hydrogen and R 3 is trifluoromethyl
  • R 2 and R 3 independently represent hydrogen, alkyl or alkoxy.
  • chemiluminescence assay makes use of 300 ⁇ M lucigenin to amplify the chemiluminescence. See Simmonds et al., Gastroenterology, cited above.
  • the assay method was validated by measuring the chemiluminescence observed in tissues exhibiting various degrees of UC or CD against the chemiluminescence observed in normal tissues. In the normal tissues, the median chemoluminescence measurement was about 8,000 photons/minute/mg wet weight. The median chemiluminescence measurements in tissues from patients with active, severe IBD, increased to as much as about 90,000 on the same scale.
  • the effect of the compounds of the present invention was demonstrated by adding a 10 -6 molar concentration of 3-(3-trifluoromethylphenyl)-4-aminoisothiazole-5-carboxylic acid to the buffer in which samples of tissue from UC patients was maintained. It was observed that the addition of the compound inhibited the production of chemiluminescence by from 8% to 70%, with a median inhibition of about 25%, indicating a corresponding reduction in the presence or activity, or both of the reactive oxygen metabolites in the tissue.
  • the treatment methods of the present invention are useful and beneficial to all patients suffering from inflammatory bowel disease, including patients with ulcerative colitis and those suffering from Crohn's disease. Both patients who are suffering from an active outbreak of IBD and those who have suffered from active IBD, but are presently in a state of remission, are benefited by the present treatment methods
  • the present method includes both therapeutic methods, for the treatment of actively suffering patients, and prophylactic methods, for the prevention of the relapse of patients who are at risk of IBD in any of its forms, but who are presently in a state of remission.
  • the general routes of administration by which the compounds are effective, and some information about the formulations of them, are taught in the Beck et al. patents, cited above.
  • oral administration of the drug is usually preferable, because of the convenience and economy of such administration.
  • the compounds may be formulated for oral administration in the usual pharmaceutical forms, such as tablets, capsules, suspensions, solutions and the like.
  • the compounds may also be administered intravenously, intramuscularly or even transdermally, if it is particularly convenient to do so, for example, for patients who are so ill that they cannot take drugs orally.
  • the compounds may be administered topically, as in the forms of suppositories or enemas, in order to place the drug in immediate contact with the affected tissues.
  • compositions for IBD are quite different, and have not previously been disclosed.
  • Such compositions are adapted to be administered rectally.
  • such formulations are in the liquid form administered as enemas and in the solid form administered as suppositories. Both formulation types are old in the pharmaceutical art and the formulation of the present compounds in such forms presents no unusual difficulties.
  • Suppositories in general, are usually prepared from low-melting solid materials, which are administered in the solid form and melt in the rectum, to release the drug which is dispersed in the solid matrix.
  • the solids from which suppositories were made were oily or waxy materials, such as cocoa butter and the like.
  • Bland petroleum and vegetable waxes have also been used, as have mixtures of vegetable oils thickened with such waxes.
  • gelling agents in modern chemistry enables such formulations to be prepared in aqueous-based materials, avoiding the administration of oily and waxy materials, which, of course, are quite foreign to the body.
  • Such an aqueous-based suppository can be prepared by dissolving or suspending the drug in water, preferably made isotonic by addition of appropriate inorganic salts, and thickening the mixture by the addition of a gelling agent such as a carboxycellulose, for example, until it has become a soft solid at room temperature but will liquify at the temperature of the body.
  • a gelling agent such as a carboxycellulose
  • the drug When the drug is to be administered as an enema, it need only be dissolved or dispersed in a small volume, such as 100 ml or less, of an aqueous mixture. It is preferable to make the mixture isotonic, to avoid any upset in the water balance of the affected tissues.
  • the vehicle for an enema may be no more complicated than physiological buffered saline. It may be convenient to prepare an enema mixture as a solid, comprising a dose of the drug with appropriate quantities of the buffering salts, to be reconstituted with deionized water at the time of use. Alternatively, if an easily water-soluble salt of the drug is chosen, the appropriate dose of the drug may simply be dissolved in physiological buffered saline and administered in that form.
  • the dose of drug to be administered in the practice of the present methods of treatment must be chosen by the attending physician, taking into account the severity of the patient's IBD, the extent of involvement of tissues, and the potency of the specific drug which is chosen. In general, it will be necessary to administer a larger dose if the administration is systemic, such as oral or parenteral, then if a topical administration directly to the affected tissue is chosen.
  • An appropriate range of doses is from about 1 to 100 mg/kg., particularly for systemic administration. When topical administration is used, a more appropriate range of doses is from about 0.2 to about 40 mg/kg. A more preferred range of doses, however, is from about 2 to about 50 mg/kg, and a still more preferred dosage range is from about 5 to about 35 mg/kg.
  • Disperse the drug in the water for use as an enema mixture Disperse the drug in the water for use as an enema mixture.
  • Cocoa butter 3 g
  • ammonium salt 500 mg
  • ammonium salt 100 mg
  • Alginate gel 2 g

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)
US07/909,852 1992-07-07 1992-07-07 Treatment of inflammatory bowel disease Expired - Fee Related US5294630A (en)

Priority Applications (11)

Application Number Priority Date Filing Date Title
US07/909,852 US5294630A (en) 1992-07-07 1992-07-07 Treatment of inflammatory bowel disease
ZA934740A ZA934740B (en) 1992-07-07 1993-07-01 Treatment of inflammatory bowel disease
AU41758/93A AU672977B2 (en) 1992-07-07 1993-07-05 Treatment of inflammatory bowel disease
CA002099789A CA2099789A1 (en) 1992-07-07 1993-07-05 Treatment of inflammatory bowel disease
ES93305298T ES2090875T3 (es) 1992-07-07 1993-07-06 Tratamiento de enfermedades inflamatorias del intestino.
AT93305298T ATE139440T1 (de) 1992-07-07 1993-07-06 Behandlung von entzündlichen darmerkrankungen
JP5166779A JPH06157310A (ja) 1992-07-07 1993-07-06 炎症性腸疾患の治療薬
EP93305298A EP0578477B1 (en) 1992-07-07 1993-07-06 Treatment of inflammatory bowel disease
DK93305298.7T DK0578477T3 (da) 1992-07-07 1993-07-06 Behandling af inflammatorisk tarmsygdom
DE69303234T DE69303234T2 (de) 1992-07-07 1993-07-06 Behandlung von entzündlichen Darmerkrankungen
GR960402479T GR3021114T3 (en) 1992-07-07 1996-09-19 Treatment of inflammatory bowel disease.

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US07/909,852 US5294630A (en) 1992-07-07 1992-07-07 Treatment of inflammatory bowel disease

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US5294630A true US5294630A (en) 1994-03-15

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US (1) US5294630A (da)
EP (1) EP0578477B1 (da)
JP (1) JPH06157310A (da)
AT (1) ATE139440T1 (da)
AU (1) AU672977B2 (da)
CA (1) CA2099789A1 (da)
DE (1) DE69303234T2 (da)
DK (1) DK0578477T3 (da)
ES (1) ES2090875T3 (da)
GR (1) GR3021114T3 (da)
ZA (1) ZA934740B (da)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6174864B1 (en) 1996-12-10 2001-01-16 Cci Corporation Methods for the prevention or treatment of inflammatory bowel diseases
US6358939B1 (en) 1999-12-21 2002-03-19 Northern Lights Pharmaceuticals, Llc Use of biologically active vitamin D compounds for the prevention and treatment of inflammatory bowel disease
US20030118329A1 (en) * 2001-12-21 2003-06-26 Pere Obrador Video indexing using high resolution still images
US6989377B2 (en) 1999-12-21 2006-01-24 Wisconsin Alumni Research Foundation Treating vitamin D responsive diseases
US20060127503A1 (en) * 2004-01-20 2006-06-15 Harly Richard F Compositions for treatment of inflammatory diseases
US20070042960A1 (en) * 1999-11-16 2007-02-22 Zymogenetics, Inc. Methods of using Zven proteins
US20070053908A1 (en) * 2002-10-07 2007-03-08 Zymogenetics, Inc. Uses of human zven antagonists
US20080219985A1 (en) * 2005-09-13 2008-09-11 Thompson Penny J Prok2 antagonists and methods of use
US20090297630A1 (en) * 2005-12-02 2009-12-03 Laboratorios Casen-Fleet, S.L. Rectal Use of a Sodium Chloride Solution as an Intestinal Cleanser
US8481760B2 (en) 2008-10-10 2013-07-09 Northwestern University Inhibition and treatment of prostate cancer metastasis
US9839625B2 (en) 2014-11-06 2017-12-12 Northwestern University Inhibition of cancer cell motility

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5199884B2 (ja) * 2006-12-06 2013-05-15 カルピス株式会社 炎症性腸疾患予防治療剤

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Cited By (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6174864B1 (en) 1996-12-10 2001-01-16 Cci Corporation Methods for the prevention or treatment of inflammatory bowel diseases
US20070172889A1 (en) * 1999-11-16 2007-07-26 Zymogenetics, Inc. Human Zven polypeptides
US7691610B2 (en) 1999-11-16 2010-04-06 Zymogenetics, Inc. Human zven polynucleotides
US7691585B2 (en) 1999-11-16 2010-04-06 Zymogenetics, Inc. Human Zven polypeptides
US20070042960A1 (en) * 1999-11-16 2007-02-22 Zymogenetics, Inc. Methods of using Zven proteins
US20070042417A1 (en) * 1999-11-16 2007-02-22 Zymogenetics, Inc. Methods of using Zven polynucleotides
US20070048805A1 (en) * 1999-11-16 2007-03-01 Zymogenetics, Inc. Methods of using Zven antibodies
US7662641B2 (en) 1999-11-16 2010-02-16 Zymogenetics, Inc. Method of using Zven antibodies
US6358939B1 (en) 1999-12-21 2002-03-19 Northern Lights Pharmaceuticals, Llc Use of biologically active vitamin D compounds for the prevention and treatment of inflammatory bowel disease
US6858595B2 (en) 1999-12-21 2005-02-22 Wisconsin Alumni Research Association Use of biologically active vitamin D compounds for the prevention and treatment of inflammatory bowel disease
US6989377B2 (en) 1999-12-21 2006-01-24 Wisconsin Alumni Research Foundation Treating vitamin D responsive diseases
US20030118329A1 (en) * 2001-12-21 2003-06-26 Pere Obrador Video indexing using high resolution still images
US20090312257A1 (en) * 2002-10-07 2009-12-17 Thompson Penny J Uses of human zven proteins and polynucleotides
US20090312258A1 (en) * 2002-10-07 2009-12-17 Lewis Katherine E Uses of human zven proteins and polynucleotides
US20070092912A1 (en) * 2002-10-07 2007-04-26 Zymogenetics, Inc. Uses of human zven antagonists
US20070078259A1 (en) * 2002-10-07 2007-04-05 Zymogenetics, Inc. Uses of human Zven proteins and polynucleotides
US20070053908A1 (en) * 2002-10-07 2007-03-08 Zymogenetics, Inc. Uses of human zven antagonists
US20070053907A1 (en) * 2002-10-07 2007-03-08 Zymogenetics, Inc. Uses of human zven antagonists
US7531311B2 (en) 2002-10-07 2009-05-12 Zymogenetics, Inc. Methods of detecting or diagnosing inflammatory bowel disease using prokineticin polynucleotides
US7592312B2 (en) 2002-10-07 2009-09-22 Zymogenetics, Inc. Methods of modulating gastrointestinal contractility
US20070087414A1 (en) * 2002-10-07 2007-04-19 Zymogenetics, Inc. Uses of human Zven proteins and polynucleotides
US7629445B2 (en) 2002-10-07 2009-12-08 Zymogenetics, Inc. Isolated nucleic acid sequence comprising SEQ ID NO: 14 and methods of using said nucleic acid sequence
US20090312256A1 (en) * 2002-10-07 2009-12-17 Penny J Thompson Uses of human zven proteins and polynucleotides
US7638507B2 (en) 2004-01-20 2009-12-29 The Board Of Regents Of The University Of Oklahoma Compositions for treatment of inflammatory diseases
US7417037B2 (en) 2004-01-20 2008-08-26 The Board Of Regents Of The University Of Oklahoma Compositions and methods of treatment for inflammatory diseases
US20060141057A1 (en) * 2004-01-20 2006-06-29 Harty Richard F Methods of treatment of inflammatory diseases
US20060127503A1 (en) * 2004-01-20 2006-06-15 Harly Richard F Compositions for treatment of inflammatory diseases
US7691832B2 (en) 2004-01-20 2010-04-06 The Board Of Regents Of The University Of Oklahoma Methods of treatment of inflammatory diseases
US20080219985A1 (en) * 2005-09-13 2008-09-11 Thompson Penny J Prok2 antagonists and methods of use
US20090297630A1 (en) * 2005-12-02 2009-12-03 Laboratorios Casen-Fleet, S.L. Rectal Use of a Sodium Chloride Solution as an Intestinal Cleanser
US8481760B2 (en) 2008-10-10 2013-07-09 Northwestern University Inhibition and treatment of prostate cancer metastasis
US8742141B2 (en) 2008-10-10 2014-06-03 Northwestern University Inhibition and treatment of prostate cancer metastasis
US9839625B2 (en) 2014-11-06 2017-12-12 Northwestern University Inhibition of cancer cell motility
US10231949B2 (en) 2014-11-06 2019-03-19 Northwestern University Inhibition of cancer cell motility
US10780076B2 (en) 2014-11-06 2020-09-22 Northwestern University Inhibition of cancer cell motility

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JPH06157310A (ja) 1994-06-03
ES2090875T3 (es) 1996-10-16
AU672977B2 (en) 1996-10-24
GR3021114T3 (en) 1996-12-31
EP0578477A1 (en) 1994-01-12
EP0578477B1 (en) 1996-06-19
ATE139440T1 (de) 1996-07-15
AU4175893A (en) 1994-01-13
DK0578477T3 (da) 1996-07-15
ZA934740B (en) 1995-01-03
DE69303234D1 (de) 1996-07-25
DE69303234T2 (de) 1996-11-21
CA2099789A1 (en) 1994-01-08

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